The classical somatomedin hypothesis states that the IGFs mediate many of the physiologic functions of growth hormone (GH). Recently, however, it has become apparent that IGF physiology in the central nervous system differs significantly from that in the periphery as unique or variant IGF peptides, receptors and binding proteins have now been described in the CNS and CSF. A new somatomedin hypothesis is being proposed which suggests that the IGF network in the brain constitutes a distinct system in which the IGFs play important roles as neurohormones, neuromodulators and neurotransmitters. The goal of this proposal is to elucidate the unique biochemistry of the CNS IGF network and to study the role of IGFs in pituitary and CNS physiology. The two specific aims of the project are to address the following questions: I. What are the unique components of the CNS IGF Network?: CNS IGF and insulin receptors will be localized by immunohistochemistry, by in situ hybridization and by antireceptor antibodies. The novel CSF IGF binding protein will be purified and further characterized and the role of binding proteins in IGF action will be assessed. The hormonal regulation of IGF and insulin receptor and IGF binding protein synthesis will be determined in the rat. The concentration of IGF peptide will be correlated with IGF mRNA abundance, and the factors which alter translatability of the various mRNA transcripts will be studies. The role of local production of IGF-I and IGF-II will be determined. II. What are the effects of in vitro and in vivo IGF-I and IGF-II administration on the regulation of the hypothalamic-pituitary-IGF axes? The role of IGF-I and IGF-II in the regulation of GH and ACTH will be studied in static and perifusion cultures. The effect of parenteral IGF-I and IGF-II on GH and IGF synthesis and secretion in the rat and human will be evaluated. The effect of IGF-I and IGF-II on brain IGF receptors and binding proteins will be examined. The acute and chronic effects of IGF administration on glucose homeostasis will be studied using the glucose clamp technique.